Hedegaardspencer7215
Protein-nucleic acid interactions play essential roles in many biological processes, such as transcription, replication and translation. In protein-nucleic acid interfaces, hotspot residues contribute the majority of binding affinity toward molecular recognition. Hotspot residues are commonly regarded as potential binding sites for compound molecules in drug design projects. The dynamic property is a considerable factor that affects the binding of ligands. Computational approaches have been developed to expedite the prediction of hotspot residues on protein-nucleic acid interfaces. However, existing approaches overlook hotspot dynamics, despite their essential role in protein function. Here, we report a web server named Hotspots In silico Scanning on Nucleic Acid and Protein Interface (HISNAPI) to analyze hotspot residue dynamics by integrating molecular dynamics simulation and one-step free energy perturbation. HISNAPI is capable of not only predicting the hotspot residues in protein-nucleic acid interfaces but also providing insights into their intensity and correlation of dynamic motion. Protein dynamics have been recognized as a vital factor that has an effect on the interaction specificity and affinity of the binding partners. We applied HISNAPI to the case of SARS-CoV-2 RNA-dependent RNA polymerase, a vital target of the antiviral drug for the treatment of coronavirus disease 2019. We identified the hotspot residues and characterized their dynamic behaviors, which might provide insight into the target site for antiviral drug design. The web server is freely available via a user-friendly web interface at http//chemyang.ccnu.edu.cn/ccb/server/HISNAPI/ and http//agroda.gzu.edu.cn9999/ccb/server/HISNAPI/.Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6"-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >-12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.As important post-translational modifications, protein cysteine modifications (PCMs) occurring at cysteine thiol group play critical roles in the regulation of various biological processes in eukaryotes. Due to the rapid advancement of high-throughput proteomics technologies, a large number of PCM events have been identified but remain to be curated. Thus, an integrated resource of eukaryotic PCMs will be useful for the research community. In this work, we developed an integrative database for protein cysteine modifications in eukaryotes (iCysMod), which curated and hosted 108 030 PCM events for 85 747 experimentally identified sites on 31 483 proteins from 48 eukaryotes for 8 types of PCMs, including oxidation, S-nitrosylation (-SNO), S-glutathionylation (-SSG), disulfide formation (-SSR), S-sulfhydration (-SSH), S-sulfenylation (-SOH), S-sulfinylation (-SO2H) and S-palmitoylation (-S-palm). Then, browse and search options were provided for accessing the dataset, while various detailed information about the PCM events was well organized for visualization. With human dataset in iCysMod, the sequence features around the cysteine modification sites for each PCM type were analyzed, and the results indicated that various types of PCMs presented distinct sequence recognition preferences. Moreover, different PCMs can crosstalk with each other to synergistically orchestrate specific biological processes, and 37 841 PCM events involved in 119 types of PCM co-occurrences at the same cysteine residues were finally obtained. Taken together, we anticipate that the database of iCysMod would provide a useful resource for eukaryotic PCMs to facilitate related researches, while the online service is freely available at http//icysmod.omicsbio.info.
To compare the efficacy of traditional and digital communication strategies in improving compliance with fixed orthodontic therapy and to investigate the effect of gender, baseline oral hygiene habits, socioeconomics, and parents' education on orthodontic compliance.
Orthodontic patients were randomly allocated to three groups. Group 1 received traditional communication including verbal and written instructions, whereas group 2 and group 3 received, in addition to traditional communication, weekly text messages or e-mails with audiovisual links, respectively. TTNPB solubility dmso Baseline demographics (age, gender, baseline oral hygiene habits, socioeconomics, and parents' education) as well as compliance indicators (treatment duration, failed appointments, incidence and total number of appliance breakages) were recorded. For statistical analysis, Pearson chi-square, independent t-test, and one-way analysis of variance were used (P < .05).
Of 120 patients (aged 12 to 18 years) recruited, 108 completed the trial (G1 = 37,hold income, and high parent education are associated with better compliance with fixed orthodontic treatment.Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16Ink4a and p21Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n = 10) compared to age-matched placebo-treated mice (n = 10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1, and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic, and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation, and microbial dysbiosis in older subjects.Dihydroorotate dehydrogenase (DHODH) is a key enzyme required for de novo pyrimidine synthesis and it is suggested as a target for COVID19 treatment due to high pyrimidine demand by the virus replication in the infected host cells as well as its proven effect of blocking of cytokine release by the immune cells to prevent inflammation leading to acute respiratory distress. There are a number of clinical trials underway for COVID19 treatment using DHODH inhibitors; however, there are only a small number of known DHODH antagonists available for testing. Here, we have applied a methodology to identify DHODH antagonist candidates, and compared them using in silico target prediction tools. A large set of 7900 FDA-approved and clinical stage drugs obtained from DrugBank were docked against 20 different structures DHODH available in PDB. Drugs were eliminated according to their predicted affinities by Autodock Vina. About 28 FDA-approved and 79 clinical trial ongoing drugs remained. The mode of interaction of these mproliferation. Those who are found experimentally effective can play an important role in COVID19 treatment. Moreover, we suggest investigating COVID19 case conditions in patients using schizophrenia and depression drugs.A Commentary on Emergency Surgery at the Epicenter of the COVID-19 Pandemic.
the hernial sac is typically a bilayer structure consisting of connective tissue lined underneath by peritoneum. Some incidental findings on it, like smooth muscle cells and heterotopic ossification, can be explained as the end-stage metaplasia from undifferentiated cells. This study aimed to search for mesenchymal stem cells in the incisional hernial sac by an immuno-histochemistry screening test.
fifteen specimens of them were submitted to histochemistry analysis using CD133 monoclonal antibodies, a specific marker of mesenchymal stem cells. The biopsies were obtained from patients submitted to pure tissue repair for incisional hernias - the transposition with the hernial sac technique (Lázaro da Silva, 1971).
two-thirds of the specimens expressed on average 20 (twenty) CD133+ cells in each one.
despite the screening nature of this study, the hernial sac may be considered a source of stem cells. This could explain those abnormal findings, and perhaps the induction of new fibroblasts in procedures that use it to optimize wound healing.
despite the screening nature of this study, the hernial sac may be considered a source of stem cells. This could explain those abnormal findings, and perhaps the induction of new fibroblasts in procedures that use it to optimize wound healing.
the onset of minimally invasive surgery, such as laparoscopic surgery, was accompanied by an increased frequency of complications, many of which were life-threatening. With the objective of minimizing morbidity and mortality and accelerating the learning curve, video laparoscopic surgery simulators were developed to improve the psychomotor skills required for these procedures.
to compare the performance of second year medical students of the Lutheran University of Brazil, in simulated videolaparoscopic surgeries performed at the Realistic Simulation Center of the Faculty of Health Sciences of Porto Alegre.
prospective cohort study with 16 medical students with no prior experience in video-surgery simulation. The students performed simulated exercises and were evaluated regarding Coordination, Navigation by Instrument and Time in the accomplishment of the procedures.
the sample consisted of 69% women and 31% men with a mean age of 23.2 years. The students obtained better results in the second simulation application.
